2015 Judson J. Van Wyk Prize Alan D. Rogol, MD, PhD

Introduced by: David B. Allen, MD University of Wisconsin School of Medicine and Public Health

Disclosures

Dr. Allen has documented that he has no relevant financial relationships to disclose or conflicts of interest to resolve.

Except, he admits that he • is heavily biased as mentee, admirer, and friend of

Dr. Rogol • still wonders if he should have accepted that

fellowship position at Virginia in 1986!

A new VWA spin

PES “All-around” award •Researcher •Mentor •Leader •Specialty advocate

Alan Rogol: the facts Height = shorter than he sounds from

across the room BMI = in the Schwarzenegger range Education: S.B. Chemistry MIT 1963

ADR: the facts Training:

• M.D. and Ph.D, Duke University 1970

• Residency: Johns Hopkins Hospital, 1971-75

• Fellowship NIH, 1972-74 Academic life and work:

• University of Virginia, Charlottesville 1975-present

• Riley Children’s Hospital • 287 peer-reviewed publications • 244 invited reviews and editorials • 39 national committees • Mentor for 18 Endocrine fellows

and countless others

ADR the Research Collaborator

Basic: whole animal endocrinology physiology

Clinical: •Neuroendocrinology of growth and

puberty •Pharmaceutical agents affecting

growth and intermediary metabolism •Neuroendocrinology of sport training

and regulation of body composition

THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 244, No. 6, Issue of March 25, pp. 1567-1575, 1969

Structural Studies on Bovine Growth Hormone I. ISOLATION AND CHARACTERIZATION OF CYANOGEN BROMIDE FRAGMENTS*

(Received for publication, November 7, 1968) ROBERT E. FELLOWS,JR. AND ALAN D. ROGOL

From The Department of Physiology and Pharmacology, Duke University Medical Center, Durham, North Carolina 27706

Partial characterization of these fragments indicates a high degree of similarity between BGH and HGH.

Vilification of Bovine Growth Hormone Udderly Unwarranted Can Bovine Growth Hormone Help Slow Global Warming? www.scientificamerican.com

Basal GH levels were high in malnourished groups and normalized after re-feeding, suggesting that lipolysis

mediated by high GH and possibly low IGF levels is an adaptation to assure fuel supply for brain and peripheral

tissue metabolism during nutritional deprivation.

Response of the pitui-tary to GHRH varies throughout the night in some GHD children. A direct relationship between the time of night and response

of pituitary to GHRH suggests that this variable response may be due to inter-mittent hypothalamic

somatostatin secretion.

Intense gymnastics training: • Does not attenuate growth of upper or lower body

segment lengths • Does not attenuate rate of pubertal growth nor

timing and tempo of the pubertal growth spurt. • Does not reduce adult height

Mentor (i.e. Coach) ADR “ Alan was my personal

trainer at meetings, ‘coaxing’ me out of bed at the crack of dawn for his 'free' weight training. Of course, I could never perform to his standards despite his nutritional recipes and formulas for success. I’m sure he considers me a failure as his athletic trainee!”

Ora Pescovitz

All-around ADR Through the miracle of

genetics (i.e. marrying Joanne), parented some very attractive kids

Is the undisputed King of countless 24/7 emails

Most are “Rogol-SPAM”: “Acknowledged. Kind regards, ADR”

Has a hard time being rough on anyone, even when fully justified

Has unsurpassed love for and devotion to PES

Kenneth C. Copeland, MD

An Ambassador for Pediatric Endocrinology

(LW)PES • Committees: Public Relations, Program Directors, History • Secretary 2004-10 • JPOC 2009 and 2013 Joint meetings

ESPE training courses in Europe, Kenya and Nigeria Endocrine Society

• Committees: Public Relations, Annual Meeting Planning, Endocrine Self-Assessment program, JCEM Best Paper Prize (chair), Development (Corporate Liaison) Steering, Nominating (chair), Hormone Foundation, Pediatric ESAP (chair)

• Executive Committee of the Council as Vice President for Clinical Practitioners.

Congratulations Alan!

2015 Judson J. Van Wyk

Prize

Judson J. Van Wyk Prize

Pediatric Endocrine Society 2015

“…Yet today I consider myself the luckiest man on the face of this earth…”

Lou Gehrig July 4, 1939

Vlatava

Vlatava (Vyšehrod, The High Castle)

Mentors • Duke

– Daniel Tosteson, MD – Robert E. Fellows, Jr., MD, Ph.D

• Johns Hopkins – Robert M. Blizzard, MD – Matthew Debusky, MD

• NIH – Saul Rosen, MD. Ph.D – Host of others

• Virginia – Robert M. Blizzard, MD – Joseph Larner, MD, Ph.D

“A short walk in the garden of auxological delights”

JM Tanner Human Growth in Context

1999

W.T.R.

W. T. R. History

• Hx of neonatal hypoglycemia and seizures

• Severe developmental delay

• Short stature; height >5 SDs below mean

• Midline abnormalities

• “Chubby”; weight 25%ile

• Undetectable TSH, low T4

Growth Curve

Patient W.T.R.,* a 3,100 gm, full-term infant was born May 16, 1945; pregnancy, labor, and delivery were uncomplicated. The mother was a 26-year-old, gravida 3, para 2 woman.

GH Prl

Pit-1

TSH

Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1 Li S, et al. Nature. 1990;347:528–533.

GH Prl

Pit-1

TSH

A Mutation in the POU-Homeodomain of Pit-1 Responsible for Combined Pituitary Hormone Deficiency Radovick S, et al. Science.1992;257:1115–1118.

x x x

• Skull x-ray- enlarged pituitary fossa

• Prolactin- 66 µg/L (normal <25)

• Mean GH- 95 ± 9.4 µg/L (normal <5)

• IGF-I- 11 U/mL (normal <2)

Pre-Operative Evaluation

7 Weeks Post Pituitary Surgery

• Mean GH- 52 ± 6.2 µg/L (normal <5)

• IGF-I- 7.7 U/mL (normal <2)

Somatotrope Hyperplasia

• Reticulin fiber pattern preserved • Somatotropes predominated; thyrotropes,

gonadotropes & corticotropes interspersed • Electron microscopy of somatotropes:

– Well developed endoplasmic reticulum & Golgi apparatus

– Densely packed with secretory granules ? Result of somatostatin excess

Reasons to Search for Ectopic GHRH Secreting Tumor

• Persistent acromegaly

• Pituitary histology

GH

Prl

0 1 2 3 4 5 6

70

60

50

40

30

20

10

0

Hours after Tumor Removal

Seru

m G

H (µ

g/L)

Effect of Removal of GHRH Secreting Pancreatic Tumor

GH Profiles of Normal Subject & GH Deficient Child Before & After Pretreatment with Pulsatile GHRH

Smith et al. J Clin Endocrinol Metab.1986;25:35.

Time (hours)

Seru

m G

H (µ

g/L)

2000 2400 0400 0800 1200

Normal Pretreatment Month 2 Month 5

10

5

0 2.5

0

10

5

0 15

10

5

0

GH Profiles of Normal Subject & GH Deficient Child Before & After Pretreatment with Pulsatile GHRH

Smith et al. J Clin Endocrinol Metab.1986;25:35.

Time (hours)

Seru

m G

H (µ

g/L)

2000 2400 0400 0800 1200

Normal Pretreatment Month 2 Month 5

10

5

0 2.5

0

10

5

0 15

10

5

0

GH Profiles of Normal Subject & GH Deficient Child Before & After Pretreatment with Pulsatile GHRH

Smith et al. J Clin Endocrinol Metab.1986;25:35.

Time (hours)

Seru

m G

H (µ

g/L)

2000 2400 0400 0800 1200

Normal Pretreatment Month 2 Month 5

10

5

0 2.5

0

10

5

0 15

10

5

0

GH Profiles of Normal Subject & GH Deficient Child Before & After Pretreatment with Pulsatile GHRH

Smith et al. J Clin Endocrinol Metab.1986;25:35.

Time (hours)

Seru

m G

H (µ

g/L)

2000 2400 0400 0800 1200

Normal Pretreatment Month 2 Month 5

10

5

0 2.5

0

10

5

0 15

10

5

0

GHRH Conclusions • GH deficiency is often due to GHRH deficiency

• GHRH acutely stimulates GH in normal and GH deficient subjects

• Once daily GHRH is safe and effectively accelerates growth velocity in the majority of GH deficient patients

• GHRH is the physiologic replacement therapy

• Sustained release preparations are now available and should be investigated in treatment of children with GHD

(N Engl J Med 2000; 343:1362-8.)

Well-defined zones in normal adrenal gland

Intermingling of chromaffin and cortical cells in salt-wasting CAH

Congenital Lipoid Adrenal Hyperplasia

• Massively enlarged adrenals filled with cholesterol esters

• Cannot convert cholesterol to pregnenolone

• Very low serum steroids • Severe salt-wasting syndrome • XY Males have female external

genitalia

CHOLESTEROL

PREGNENOLONE

Patients with lipoid CAH can’t convert cholesterol to pregnenolone, yet have normal P450scc genes. What gene is mutated?

P450scc

Lin et al. J Clin Invest.1991;88:1955.

Add Dong’s picture here!

Dong Lin

Lipoid CAH: The StAR Knockout of Nature

Lin et al. Science.1995;267:1828.

Steroidogenic Acute Regulatory Protein (StAR)

• Triggers acute steroidogenic response in adrenals and gonads

• Short half-life • Induced by cAMP • 37 kDa form with mitochondrial leader; 30 kDa

intramitochondrial form • Increases flow of cholesterol from outer

mitochondrial membrane to P450scc

Clark et al. J Biol Chem.1994;269:28314.

Tibi gratias ago

(thank you)